Bendamustine

Bendamustine hydrochloride is an alkylating agent recently approved by the FDA for treatment of Chronic Lymphocytic Leukemia (CLL). The FDA approved bendamustine (trade name Treanda) based on a randomized, controlled, multicenter trial using either bendamustine or chorambucil, another alkylating agent, as initial treatment for CLL. This trial showed good results were obtained with bendamustine. A more recent study further found that CLL patients treated with bendamustine as a first-line therapy did better than those treated with the older drug chlorambucil.

In Oct 2008, the FDA extended its approval for bendamustine to treat indolent B-cell non-Hodgkin’s lymphoma (NHL). Indolent NHL strikes about 30,000 people in the US every year. The FDA action was for people whose NHL had not responded to treatment with rituximab (Rituxan).

Bendamustine was developed in East Germany during the 1960’s. It has been used there to treat more than 20,000 cancer patients, including those with multiple myeloma, non-Hodgkin’s lymphoma and solid cancers. Studies are ongoing in Germany, the United States, and other countries to see how well bendamustine works for cancers other than CLL.

Bendamustine is a “bifunctional mechlorethamine derivative.” The drug and its derivatives break down into alkyl groups. The alkyl groups bond with substances inside of tumor cells. This eventually leads to cell death. (Alkylating agents are one of the oldest types of chemotherapy medicine.) The exact mechanism by which bendamustine kills tumor cells is not known. In addition to being an alkylating agent, it also has similarities with other cancer treatment drugs, nucleoside analogs and purine analogs. Indeed, it has structural similarities to other alkylating agents and antimetabolites used in cancer treatment, but one good thing is that patients who develop resistance to those other drugs (e.g. carboplatin, etc.) don’t automatically become resistant to bendamustine.

Bendamustine has also been investigated for use as a salvage therapy in advanced breast cancer. Its low toxicity and clinical trial results that show increases in patient survival times have drawn the attention of cancer researchers, who suggest that a weekly administration of the drug may be beneficial for breast cancer that has already been treated with taxol or antibiotics.

This medication differs from many other chemotherapy agents in that it can be given infrequently. Indeed, a recent study suggested that once-every-three weeks administration of bendamustine can be effective. The medication also promises to be an advance in the quest to develop personalized chemotherapy based on individual patient characteristics, although that still remains a ways off.

Treatment

Patients with CLL do not always need treatment. CLL is usually diagnosed in older patients (median age 64 years). In some patients, perhaps a third, CLL never really progresses. These patients live for many years and die from another cause. In another group of patients the disease starts of slowly and then worsens, necessitating treatment. In the last group, CLL is immediately aggressive and treatment must be started as soon as the diagnosis is made.

There are staging systems to help decide whether or not a patient needs treatment. For the study that led to FDA approval of bendamustine, only CLL patients who definitely needed treatment were included. The patients had symptoms including, for example, not enough red blood cells, weight loss of 10% or more, severe night sweats, fever 100.5 or higher, bulky lymphadenopathy (large lymph nodes) or progressive disease.

The patients were treated with either chlorambucil, a well-known alkylating agent, or bendamustine. 59% of the patients taking bendamustine responded to the treatment, versus 26% of the patients taking chlorambucil. 8% of those taking bendamustine had complete disappearance of the cancer versus less than 1% of those taking chlorambucil.

However, 89% of the patients taking bendamustine suffered serious side effects, whereas those taking chlorambucil had 79%. More than 15% suffered from fever, neutropenia (low neutrophil count), thromobocytopenia (low platelet count), leucopenia (low white blood cells), nausea, vomiting, and anemia. More patients treated with bendamustine needed blood transfusions. Patients on bendamustine dropped out of the study most frequently because of hypersensitivity (allergy) or high fever. There was no significant difference in the number of deaths in the two groups.

For non-Hodgkin’s lymphoma (NHL), bendamustine is also administered by injection. Cephalon reports that the drug stopped progression of this slow-growing cancer for a median on 9.3 months in a clinical trial.

The FDA approved bendamustine only for CLL and indolent non-Hodgkin’s lymphoma at this time. It is manufactured in the Netherlands for Cephalon, Inc. It has not been proven to be better first-line treatment for CLL relative to any treatment except chlorambucil. The ongoing studies ongoing in Europe and the United States may clarify how bendamustine might be used to treat other malignancies.

Physicians prescribing the drug must follow the proper protocols. The recommended dose of bendamustine is 100 mg/meter squared, given intravenously on day one and day two of a 28 day cycle, for a total of up to 6 cycles. Bendamustine comes as a single-use vial containing 100 mg of the drug as a lyophilized powder. It must first be mixed with 20 milliliters of Sterile Water. It is now at a concentration of 5mg/mL. The amount determined for treatment must then be mixed with 5000 mL of 0.9% Sodium Chloride Injection (normal saline) and then given to the patient intravenously over a 30 minute period. If during any of the preparation, particulate matter is observed, the product cannot be used. Once mixed it can be stored for 24 in a refrigerator or up to 3 hours at room temperature and in light.

Bendamustine comes with warnings about serious adverse reaction. It may cause myelosuppression, in which not enough blood cells are made. These may necessitate stopping the drug, and monitoring the blood cells. Treatment may be tried again if the blood cells recover. Signs of infection and fever need immediate aggressive treatment. Allergy to the drug can be mild or severe, including anaphylactic reactions. The drug should not be used if there has been a severe reaction. For milder reactions, patients can be pretreated with antihistamines, steroids, and antipyretics before the next dose. Tumor lysis syndrome, in which the large amount of dying tumor cells flood the body and kidneys can occur. This can cause kidney failure and death. Using allopurinol for patients at risk for the syndrome is recommended. Severe skin reactions can occur. Bendamustine should never be used during pregnancy.

The treatment protocol for bendamustine tells doctors when to withhold the medication and how to handle the adverse reactions. There are also instructions for how to modify doses in patients with poor liver or kidney function.

As a bifunctional mechlorethamine derivative, bendamustine was created explicitly to combine alkylating properties of mechlorethamine and the purine antimetabolite properties of benzimidazole.

Patients are told to be aware of the possibility of an allergic reaction. They should tell their doctors immediately if they experience rash, facial swelling or difficulty breathing during or after treatment. A mild rash can be treated. Severe rashes need to be reported. Patients will need monitoring of their blood counts. It is very likely that they will have lowered amounts of various blood cells during treatment, leading to fatigue, shortness of breath, bleeding, fever or other evidence of infection. All of these symptoms should be immediately reported to the treating doctor. If they experience fatigue, patients are warned not to drive or operate machinery. Nausea and vomiting can be treated by the doctor, as can diarrhea. There symptoms are common to alkylating agents, even though research suggests that bendamustine has different mechanistic features from other alkylating agents (which could explain its distinct clinical efficacy profile). The side effects may just be common to all alkylating chemotherapy agents.

Currently there are clinical trials investigating bendamustine as first-line cancer treatment, and others are using it to treat cancers that are resistant to other chemotherapeutic agents. A number of trials involve patients with non-Hodgkin’s Lymphoma who have failed other treatment. Bendamustine is being used with other drugs to treat metastatic breast cancer, small cell lung cancer, follicular lymphoma, other lymphomas and leukemias. These trials are going on in the United States, Canada, Japan and Europe and other countries. Many are still recruiting patients.

As these studies finish, it is likely that the FDA will approve bendamustine for other cancer treatment.

Chronic Myelogenous Leukemia and Bendamustine

Chronic myelogenous leukemia, or chronic myeloid leukemia, is an extremely rare type of cancer that affects the blood cells. In this condition, the bone marrow produces an abundance of abnormal white blood cells. Unlike other forms of leukemia, this type of cancer advances more slowly and gradually gets worse over a long period of time. Adults are most commonly diagnosed with chronic myelogenous leukemia, although it can affect children in rare cases.

Prevalence

According to the American Cancer Society, 10-15 percent of all leukemia’s are diagnosed as chronic myelogenous leukemia. For the typical person, there is a 1 in 625 chance that they will develop chronic myelogenous leukemia at some point during their lifetime. The typical age of onset for this disease is around 65, and as of 2010, it is estimated that more than 4,870 people will receive a diagnosis of chronic myelogenous leukemia. This disease is slightly more common in men than women and is more likely to affect whites in comparison to African-Americans.

Symptoms

The symptoms of chronic myelogenous leukemia often mimic the common symptoms of cancer in general. These symptoms include rapid weight loss, fever, loss of appetite, paleness, night sweats, constantly feeling drained of energy, bleeding easily and pain or pressure on the left side of the ribs. Since these symptoms are very common to other forms of cancer, they are very hard to detect and often do not become noticeable until the disease has progressed to the most advanced stage.

Phases

Doctors place chronic myelogenous leukemia into three phases and these classifications are made on how advanced the disease has progressed once a diagnosis has been made. The first stage of this disease is the chronic phase and the majority of people are diagnosed once their cancer has reached this stage. Symptoms are relatively mild during this stage and often go unnoticed by the patient

The second stage is the accelerated phase and it is during this time when symptoms of the disease become the most noticeable. Weight loss, fevers and lack of appetite are the most common symptoms during this stage as the disease begins to progress more rapidly.

The blast phase is the third and final stage of this disease and it is the most advanced form of chronic myelogenous leukemia. Bleeding, infection and stomach pain are the most common symptoms once the disease has progressed to this stage. It is possible for the cancer to have spread to other organs during this phase and progresses rapidly if left untreated.

Diagnosis

If a person presents with some of the symptoms of chronic myelogenous leukemia, a doctor will conduct blood tests and take samples of bone marrow. Blood tests are used to check for an extremely high white blood cell count and a physician may also conduct a physical exam in which they will feel a person’s lymph nodes and check their abdomen area for any abnormalities.

Chemotherapy Agents

Today’s arsenal of chemotherapy agents includes many different classes of medicines. Researchers continue to find and test new drugs.